Enaminones are versatile synthetic intermediates that are easily converted into a wide variety of functional groups, including (but not limited to) .beta.-aminoketones, .beta.-hydroxyketones, alkyl-substituted enones, and numerous heterocycles including isoxazoles, pyrazoles, pyrimidines, pyridines and thiophenes. Enaminones are of times used in the production of compounds of commercial importance (pharmaceuticals, insecticides, dyestuffs, etc.).
Enaminones can be synthesized by a variety of methods including the reaction of an amine with a 1,3-diketone, a 3-keto ester, a vinylogous ester, a vinylogous acid chloride, a .beta.-dialkoxy ketone, a .beta.-cyanovinyl ketone, an acetylenic ketone, by the condensation of a ketone with N,N-dimethylformamide acetal, by the acylation of enamines, by reaction of ketene with enamines, by reaction of oxime sulfonates with silyl enol ethers, by the palladium assisted amination of an olefin, by the palladium catalyzed dehydrogenation of a .beta.-amino ketone, or by the Mannich reaction of a ketone with a secondary amine and an orthoester. The preparation and use of enaminones has been the subject of two reviews: Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277; Kucklaender, U. "Enaminones as Synthons", in Chemistry of Enamines, Rappoport, Ed., Vol. 1, pp. 523-636, Chichester, UK: Wiley 1994!.
Functionalized propargylic amines can be conveniently prepared by the copper-catalyzed Mannich reaction of terminal acetylenes with formaldehyde and amines (Mannich, Chem. Ber. 1933, 66, 418) or, in the case of 3-aryl or 3-vinyl substituted prop-2-ynyl amines, by palladium-catalyzed couplings of 1-amino-prop-2-ynes with aryl or vinyl halides or triflates (Sanogashira, et.al. Tetrahedron lett. 1975, 4467; Unroe, et.al. Synthesis 1987, 981; Stille, J. K. Angew. Chem., Intl. Ed. Engl. 1986, 25, 508; Scott, et.al. Acc. Chem. Res. 1988, 21, 47; Kalinin, V. N. Synthesis 1992, 413; Ritter,K. Synthesis 1993, 735). These amines can be easily converted into the respective amine N-oxides by any of a number of standard oxidative procedures (as discussed in Albini, A. Synthesis 1993, 263) or with dioxirane reagents (reviewed in Murray, R. W. Chem. Rev. 1989, 1187).
Although the precise mechanism by which a propargylic amine N-oxide is converted into an enaminone product has not been rigorously determined, it likely resembles two known processes; the thermal 2,3!-sigmatropic rearrangement of propargylic amine N-oxides and the conversion of certain isoxazoles into enaminones. A proposed mechanism is shown below: ##STR2##
The thermal conversion by 2,3!-sigmatropic rearrangement of propargylic amine N-oxides to hydroxyl amine O-allenyl ethers is a known reaction (Equation 1, below; Craig, et.al. Tetrahedron Lett. 1979, 4025; Hallstrom, et.al. Tetrahedron Lett. 1980, 667; Khuthier, A-H, et.al. J. Chem. Soc. Chem. Commun. 1979, 9). In each instance where this 2,3!-sigmatropic rearrangement has been reported, the reactions were performed either neat or in aprotic solvents (e.g. dimethylformamide, diethyl ether, tetrahydrofuran, carbon tetrachloride) and the formation of enaminone products has not been disclosed. ##STR3##
Substituted enaminones can result from the hydrolytic breakdown of certain substituted isoxazolines (Equation 2, below), as described by Liguori, et.al. Tetrahedron 1988, 44, 1255. The isoxazolines of Liguori et al. were prepared by the 1,3-dipolar cycloaddition reaction of C-benzoyl-N-phenylnitrone with alkynes (formed as a mixture with its regioisomer). It appears that the substitution pattern about the isoxazoline ring influences the outcome of this hydrolytic reaction. This process is an isolated example of enaminone formation from isoxazolines and is not a generally applicable nor synthetically useful transformation. ##STR4##
The present invention provides a novel synthesis of enaminones from propargylic amine N-oxides upon exposure to hydroxylic solvents. This new method of enaminone synthesis provides a convenient alternative to existing methods and further extends the range of starting materials that can be converted into enaminone products.